UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although molecular and cytogenetic studies strongly point to the role of oncogenes, the mechanisms underlying the development of MDS and their progressive evolution to AML are still largely unknown. It has been postulated that AML has a preleukemic stage and a multi step pathogenesis, with the preleukemic stem cell able to undergo clonal evolution, with the acquisition of karyotypic abnormalities, leading to the development of acute leukemic subclones. The activations of the ras oncogenes or inactivation of the p53 anti-oncogene by point mutations have been described recently in several cases of MDS as well as AML, suggesting a critical role for these alterations in the development of these myelogenous leukemias. We reported previously establishment of a leukemic cell line, SKM-1, from the patient who initially possessed multiple point mutations of ras genes but lost these mutations during disease progression to myelomonocytic leukemia with acquisition of chromosomal abnormalities involving the p53 anti-oncogene. This process is characterized by genetic instabilities probably due to the failure of their DNA repairment leading to abnormal control of cell proliferation and differentiation. Studying this cell line, SKM-1, is a promising approach to understand the mechanisms of the initiation, disease progression, alterations of DNA repairment, and genetic instability in MDS and myelogenous malignancies.
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PMID:The SKM-1 leukemic cell line established from a patient with progression to myelomonocytic leukemia in myelodysplastic syndrome (MDS)-contribution to better understanding of MDS. 858 Aug 5

To determine the prevalence of activated rasoncogenes (N-ras, Harvey-ras Kirsten-ras), DNA derived from peripheral blood of 51 patients with myelodysplastic syndrome (MDS) was investigated. The method was based on the polymerase chain reaction (PCR) technique to amplify DNA, followed by restriction fragment length polymorphism (RFLP) analysis. Among the French-American-British (FAB) subtypes, N-ras mutations were found in two patients with refractory anemia with excess of blasts (RAEB), in one patient with refractory anemia with excess of blasts in transformation (RAEB-t), and in two patients with chronic myelomonocytic leukemia (CMML). MDS patients with a mutation at codon 12 of the N-ras gene showed shorter survival duration than other MDS patients of the same FAB subtypes, although these findings proved to be not statistically significant (P > 0.1). Interestingly, all but one patient with N-ras mutation developed acute myelogenous leukemia (AML). In conclusion, the presence of mutation at codon 12 of the N-ras gene might serve as a negative prognostic factor at diagnosis of MDS.
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PMID:Codon 12 ras mutations in patients with myelodysplastic syndrome: incidence and prognostic value. 903 9

A conventional and a computer search of the literature yielded 627 sequenced point mutations in the ras and p53 genes in 575 patients with leukaemia and myelodysplasia (MDS) out of a total of 4214 investigated. ras Mutations predominated in myeloid leukaemia and were more common in the disease in relapse than at presentation. There was no clinical, or haematological difference or difference in survival between ras positive and ras negative patients with acute myeloid leukaemia (AML) in adults or children, but ras mutations carried a poorer prognosis in childhood acute lymphocytic leukaemia and an increased risk of leukaemia in MDS. p53 mutations predominated in lymphoid leukaemia and were several fold more frequent in leukaemia in relapse than in the de novo disease, were associated with loss of the normal p53 allele (monosomy 17) in > 50% of cases and carried a poor prognosis in AML, MDS and chronic lymphatic leukaemia and a 3.8-fold increase risk of death in T cell acute lymphocytic leukaemia. There were 163 transitions for every 100 transversions, the expected number being ca 50. Consideration of the molecular mechanisms by which nitrous acid produces transitions allows transitions resulting from the deamination of cytosine to be distinguished from those resulting from the deamination of adenine. The former constitute 84.67% and the latter 15.33% of the 372 transitions present. Again purine-->pyrimidine and pyrimidine-->purine transversions form 80.35 and 19.65%, respectively, of the 228 transversions present. The possible bearing of this highly non-random distribution on the aetiology of point mutations in leukaemia and myelodysplasia is discussed.
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PMID:The non-random distribution of point mutations in leukaemia and myelodysplasia--a possible pointer to their aetiology. 927 67

The purpose of this review is to give an update of the recent progress in research on erythropoietin (Epo), the hormone that regulates red blood cell production. Epo is a glycoprotein with a molecular mass of approx 30 kDa, which circulates in plasma of the human with 165 amino acids with three N-linked and one O-linked acidic oligosaccharide side chains in the molecule. Both the alpha (39% CHO) and beta (24% CHO) forms are available for clinical use, and there does not appear to be any difference in the pharmacokinetics of these two forms of Epo. Radioimmunoassays and enzyme-linked immunoabsorbant (ELISA) assays are available in a kit form. Serum levels of Epo in normal human subjects range between 1 and 27 mmu/ml or approx 5 pmol/l. It seems clear that the cells in the adult mammalian kidney which produce Epo are the interstitial cells in the peritubular capillary bed and the perivenous hepatocytes in the liver. Expression of the human Epo gene sequences that direct expression in the kidney are located 6-14 kilobases 5' to the gene; whereas the sequences that control hepatocyte-specific expression are located within 0.7 KS to the 3'-flanking region and 0.5 KS to the 5'-flanking region. The signal transduction pathways postulated to be involved in the expression of Epo are: kinases A, G and C; both a constitutive factor and a second hypoxia-inducible factor-1 (HIF-1) located in the 5' end of an hypoxia inducible enhancer region of the Epo gene; and reactive oxygen species. The primary target cell in the bone marrow acted on by Epo is the colony-forming unit erythroid (CFU-E) which has the highest number of Epo receptors. It has been postulated that Epo decreases the rate which Epo-dependent progenitor cells undergo programed cell death (apoptosis). There are two major signal transduction pathways activated by the Epo receptor: the JAK2-STAT5 pathway and the ras pathway. Both pathways involve tyrosine phosphorylation. The approved clinical uses of Epo are the anemias associated with end-stage renal disease, cancer chemotherapeutic agents, and patients with HIV infection receiving AZT. Other anemias reported to respond to Epo therapy are anemia of prematurity, rheumatoid arthritis, and myelodysplasia. Other uses of Epo under investigation are in perioperative surgery and preoperative autologous blood donation.
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PMID:Erythropoietin: physiologic and pharmacologic aspects. 940 40

A cytogenetic and N-ras point mutation study was done in patients with primary myelodysplastic syndrome (MDS) from Rio de Janeiro, Brazil, in order to evaluate the progression of preleukemic states to overt leukemia. Cytogenetic analysis was performed in 50 patients with MDS and clonal chromosomal abnormalities were detected in 19 (38%) of them. Patients with refractory anemia (RA) or with ringed sideroblasts (RARS) presented normal karyotypes or single abnormalities as del(5q) or -Y, while patients in more advanced states as RA with excess of blasts (RAEB), RAEB in transformation (RAEB-t) and chronic myelomonocytic leukemia (CMML) showed complex karyotypes and single abnormalities involving chromosomes 7 or 8, which were related to poor prognosis and elevated risk of transformation to acute myeloid leukemia (AML). The frequency of ras activation was studied in these 50 patients with MDS. Samples of bone marrow were screened for oncogenic point mutations by DNA amplification followed by oligonucleotide hybridization analysis (PCR-ASO) at codon 12 of N-ras proto-oncogene. We detected N-ras point mutations in 21 patients (42%). Progression from MDS to AML was observed in 9 patients (18%). The correlation analysis between N-ras point mutations and specific chromosomal abnormalities indicated that although mutated N-ras was found in cells with del(5q) and monosomy 7, cells with those abnormalities and normal N-ras were also identified. Otherwise trisomy of chromosome 8 showed a correlation with N-ras point mutations and in all cases, patients showed progression of MDS to AML during the follow-up study. MDS comprises a heterogeneous group of hematopoietic disorders and probably several steps are implicated in the evolution to AML. In this work we suggest that one possible pathway of leukemogenesis in MDS includes N-ras point mutations in association with trisomy of chromosome 8.
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PMID:Correlation of N-ras point mutations with specific chromosomal abnormalities in primary myelodysplastic syndrome. 959 69

The activity of topotecan was evaluated in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (n = 30) or CMML (n = 30) were treated. Their median age was 66 years, with 50 patients (83%) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50% of patients and thrombocytopenia of less than 50 x 10(9)/L in 50%. Topotecan was administered as 2 mg/m2 by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum tolerated dose level (1-2 mg/m2 by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved in 11 of 30 patients with MDS (37%) and in eight of 30 with CMML (27%). A CR was achieved in 10 of 23 patients with previously untreated MDS (43%). Eight of 11 patients who presented with cytogenetic abnormalities (five of which involved chromosome 5 and/or 7 abnormalities) and achieved CR, were evaluated cytogenetically in CR: all were cytogenetically normal in CR. Characteristics associated with a higher CR rate were lack of previous chemotherapy, absence of ras oncogene mutations, and presence of less than 10% monocytes in either peripheral blood or bone marrow. In contrast, CR rates were similar by different agent groups, by different karyotype abnormalities, and by other pre-therapy peripheral blood counts. Non-myelosuppressive side effects were mucositis in 67% of patients (severe [grade 3-4] 23%), diarrhea in 38% (severe 17%), and nausea and vomiting in 28% (severe 5%). Febrile episodes during neutropenia occurred in 85% of patients and documented infections in 47 %. Mortality in the first four weeks was 20%. With a median follow-up duration of 31 months, the 12 month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. In summary, topotecan has significant single-agent activity in MDS and CMML. Complete responses associated with topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging. Future strategies to optimize topotecan's role include combination regimens with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).
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PMID:Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. 992 42

Partial deletion of the long arm of chromosome 5, del(5q), is the cytogenetic hallmark of the 5q-syndrome, a distinct subtype of myelodysplastic syndrome-refractory anemia (MDS-RA). Deletions of 5q also occur in the full spectrum of other de novo and therapy-related MDS and acute myeloid leukemia (AML) types, most often in association with other chromosome abnormalities. However, the loss of genetic material from 5q is believed to be of primary importance in the pathogenesis of all del(5q) disorders. In the present study, we performed fluorescence in situ hybridization (FISH) studies using a chromosome 5-specific whole chromosome painting probe and a 5q subtelomeric probe to determine the incidence of cryptic translocations. We studied archival fixed chromosome suspensions from 36 patients with myeloid disorders (predominantly MDS and AML) and del(5q) as the sole abnormality. In 3 AML patients studied, this identified a translocation of 5q subtelomeric sequences from the del(5q) to the short arm of an apparently normal chromosome 11. FISH with chromosome 11-specific subtelomeric probes confirmed the presence of 11p on the shortened 5q. Further FISH mapping confirmed that the 5q and 11p translocation breakpoints were the same in all 3 cases, between the nucleophosmin (NPM1) and fms-related tyrosine kinase 4 (FLT4) genes on 5q35 and the Harvey ras-1-related gene complex (HRC) and the radixin pseudogene (RDPX1) on 11p15.5. Importantly, all 3 patients with the cryptic t(5;11) were children: a total of 3 of 4 AML children studied. Two were classified as AML-M2 and the third was classified as M4. All 3 responded poorly to treatment and had short survival times, ranging from 10 to 18 months. Although del(5q) is rare in childhood AML, this study indicates that, within this subgroup, the incidence of cryptic t(5;11) may be high. It is significant that none of the 24 MDS patients studied, including 11 confirmed as having 5q-syndrome, had the translocation. Therefore, this appears to be a new nonrandom chromosomal translocation, specifically associated with childhood AML with a differentiated blast cell phenotype and the presence of a del(5q).
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PMID:A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. The UK Cancer Cytogenetics Group (UKCCG) 1039 45

Background: Mutations in members of the ras gene family (H-ras, K-ras, and N-ras) have been identified in various human malignancies. A variety of techniques have been used to test for ras mutations. Methods and Results: A simplified reverse dot blot (RDB) assay was used in this study. Polymerase chain reaction products were hybridized to nitrocellulose membrane-fixed synthetic probes (20 nucleotides long) specific for codons 12, 13, and 61 of H-, K-, and N-ras mutations and their wild-type sequences. No special treatment or modification of the probes was necessary to obtain adequate results in overnight film exposure when the polymerase chain reaction was carried out using (32)P-end labeled primers. It was demonstrated that this simplified RDB assay can also be used with fluorescein-11-dUTP and a chemiluminescence detection system. The RDB assay is more reliable than the single-strand conformation polymorphism (SSCP) assay. By comparison, the SSCP assay is significantly less sensitive and less specific. It was confirmed with sequencing that 11 (12%) of 93 SSCP assays were false positive and 2 (2%) were false negative, whereas no false positive or false negative RDB assay was detected. The RDB assay also provides more additional detailed information about the specific point mutation and amino acid change, which may have clinical implications in some tumors. Conclusions: The RDB assay is very sensitive and able to detect mutations when the mutant allele is in 1% of the cells and can be used to detect minimal residual disease, particularly in some cases of leukemia and myelodysplasia.
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PMID:Simplified Reverse Dot Blot Analyses for Detecting of ras Oncogene Mutations. 1046 6

A mutation detection strategy based on multiplex PCR followed by multiplex allele-specific oligonucleotide probe ligation was developed to detect single nucleotide substitutions in ras oncogenes, a common genetic abnormality in many human cancers. Mutation-specific probes are synthesized for each possible single-base, nonsilent mutation in codons 12, 13, and 61 of H-, K-, and N-ras oncogenes. Mutations are identified by competitive oligonucleotide probe ligation to detect normal and/or mutant genotypes in one reaction. Three probes (one common and two allelic probes) are needed for analysis of each mutation. Probes hybridized to target ras oncogene DNA are joined by a thermostable ligase if there are no mismatches at their junctions; temperature cycling results in a linear increase in product. Common probes are labeled with fluorochromes, and allelic probes each have different lengths. Ligation products are analyzed by denaturing polyacrylamide gel electrophoresis on a fluorescent DNA sequencer. We have applied this technology to identify ras mutations in pancreatic cancers and lung cancers and in patients with myelodysplastic syndromes and leukemias.
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PMID:Fluorescent oligonucleotide ligation technology for identification of ras oncogene mutations. 1089 13

Standard antileukemic chemotherapy induces complete remission in approximately half of patients with high-risk (HR) myelodysplastic syndrome (MDS). Intensification of induction therapy by the use of intermediate- or high-dose cytosine arabinoside in combination with fludarabine, idarubicin, or topotecan seemingly improved complete response (CR) rates, particularly in patients with poor prognosis karyotypes. The various high-intensity regimens appear to be comparable in inducing CR, although some are better tolerated with low mortality even in advanced-age populations with MDS. The encouraging early results with new agents, eg, topoisomerase inhibitors (topotecan) and hypomethylating agents (5-azacytidine), have been disappointing because long-term follow-up has shown continuous relapses. Regardless of the intensity of chemotherapy, remissions are short, even with continuation of intensive postremission therapy. Long-term disease-free survival remains dismal. In a large population with HR MDS treated with high-dose chemotherapy, only 5% of patients were alive at 3 years, and a majority of survivors were the younger patients with diploid karyotype refractory anemia with excess blasts in transformation. Further intensification of either induction chemotherapy or postremission therapy is unlikely to improve results with current drug combinations. With these results at hand, the role of intensive chemotherapy in the management of MDS remains controversial. Because CR status is associated with clinical benefits and possibly better survival, induction of CR should remain an important aim for HR MDS. The intensive combination chemotherapy may be integrated as an initial part of the management of HR MDS, as an alternative for patients not eligible for allogeneic bone marrow transplantation (BMT). Regimens with low early mortality, eg, topotecan plus intermediate dose Ara-C, could also be used to reduce tumor load prior to allogeneic BMT. Induction of CR should be attempted with the most effective and best tolerated regimens, particularly, but not only, in younger patients with good performance status regardless of karyotype. Postremission therapy remains a major challenge. It should involve either allogeneic BMT or investigational approaches to eliminate or control the minimal residual disease with different mechanisms In elderly patients, allogeneic "minitransplant" is an investigational alternative seeking to exploit graft-versus-tumor reaction. New agents, such as farnesyl transferase inhibitors (ras inhibitors), drug-antibody conjugates (Myelotarg), thalidomide, arsenic trioxide, maintenance chemotherapy with hypomethylating agents, or oral topoisomerase inhibitors along with agents modulating factors affecting growth and differentiation, should be explored to maintain remission with minimal compromise of quality of life. Although prognostic scoring systems such as the new International Prognostic Scoring System (IPSS) do not predict for initial response, IPSS continues to predict survival in patients treated with high-dose chemotherapy. Although activity of new agents could be rapidly assessed in single-arm pilot studies, the final merit of high-dose chemotherapy could be assessed only in well-designed randomized trials with patients assigned according to risk-based classification and evaluated for response by generally accepted and standardized criteria.
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PMID:Intensive chemotherapy for patients with high-risk myelodysplastic syndrome. 1103 61

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